CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease
- 18 October 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in Inflammatory Bowel Diseases
- Vol. 25 (11), 1788-1795
- https://doi.org/10.1093/ibd/izz103
Abstract
Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.Keywords
Funding Information
- National Institutes of Health (P30 DK034854, AI50950)
- Leona M. and Harry B. Helmsley Charitable Trust
This publication has 28 references indexed in Scilit:
- Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 DeficiencyGastroenterology, 2019
- Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined ImmunodeficiencyFrontiers in Immunology, 2018
- The 2017 IUIS Phenotypic Classification for Primary ImmunodeficienciesJournal of Clinical Immunology, 2017
- Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutationsThe Journal of Experimental Medicine, 2016
- Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutationsNature Medicine, 2014
- Capping protein regulators fine-tune actin assembly dynamicsNature Reviews Molecular Cell Biology, 2014
- Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and TherapyGastroenterology, 2012
- Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)Blood, 2011
- The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3Nature Genetics, 2001
- Differential requirements for CD28 and CD40 ligand in the induction of experimental autoimmune myasthenia gravisEuropean Journal of Immunology, 1998